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Pharmacokinetic Properties and Safety Profile of Histamine Dihydrochloride Injection in Chinese Healthy Volunteers: A Phase I, Single-center, Open-label, Randomized Study
Li, Jiapeng1; Huang, Xiaojun2; Wang, Qian1; Jing, Shan3; Jiang, Hao2; Wei, Zhongna1; Zang, Yannan1; Liu, Yang1; Zhao, Libo1; Fang, Yi1; Feng, Wanyu1
关键词Chinese Healthy Volunteers Histamine Dihydrochloride Pharmacokinetics Safety
刊名CLINICAL THERAPEUTICS
2015-10-01
DOI10.1016/j.clinthera.2015.07.017
37期:10页:2352-2364
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Pharmacology & Pharmacy
研究领域[WOS]Pharmacology & Pharmacy
关键词[WOS]ACUTE MYELOID-LEUKEMIA ; POST-CONSOLIDATION IMMUNOTHERAPY ; LIQUID-CHROMATOGRAPHY ; CEREBROSPINAL-FLUID ; MASS-SPECTROMETRY ; INTERLEUKIN-2 ; CANCER ; METABOLITES ; METHYLTRANSFERASE ; RELAPSE
英文摘要

Purpose: Histamine dihydrochloride (HDC) injection has been approved in Europe for the treatment of adults with acute myeloid leukemia, used in combination therapy with the T-cell-derived cytokine interleukin-2. Despite years of clinical applications of HDC in Europe, no data are available on its tolerability and pharmacokinetic properties in Chinese patients. The objective of this study was to determine the safety profile and pharmacokinetic properties of HDC in Chinese healthy volunteers (HVs).

Methods: In this Phase I, single-center, open-label, randomized study, 20 Chinese HVs were randomized to receive a single dose of 0.5 or 1.0 mg HDC via a 10-minute subcutaneous injection. Whole-blood and urine samples were collected at designated time points after dosing. Plasma and urine concentrations of histamine and metabolite N-methyl histamine were measured using a validated HPLC-MS/MS method. Pharmacokinetic parameters were estimated through noncompartmental procedures based on concentration-time data. Adverse events and evaluation of clinical laboratory tests were used to assess the safety profile. The pharmacokinetic profile for a single-dose of 1.0 mg HDC in Chinese HVs was compared with that in Western HVs.

Findings: No severe adverse events occurred in this study, and the severity of all adverse events was grade I according to the Common Terminology Criteria for Adverse Events, version 4.0. For the pharmacokinetic parameters of histamine at the 0.5-mg and 1.0-mg dose levels, t(1/2) was 0.50 and 1.02 hours; T-max was 0.15 and 0.14 hours; mean C-max was 26.59 and 71.01 nmol/L; AUC(0-t) was 8.35 and 20.43 nmol/h/L; AUC(0-infinity) was 9.61 and 22.69 nmol/h/L; accumulated amount excreted in urine within 24 hours was 125.93 and 145.52 nmol; and maximum urine excretion rates were 21.85 and 38.94 nmol/h, respectively. For N-methyl histamine at the 0.5-mg and 1.0-mg dose levels, t1/2 was 0.58 and 0.66 hours; T-max was 0.28 and 0.26 hours; mean C-max was 17.01 and 23.54 nmol/L; AUC(0-t) was 7.72 and 17.08 nmol/h/L; AUC(0-infinity) was 9.01 and 19.62 nmol/h/L; accumulated amount excreted in urine within 24 hours was 331.7 and 583.21 nmol; and maximum urine excretion rates were 53.29 and 133.53 nmol/h, respectively.

Implications: Both single-dose 0.5 mg and 1.0 mg HDC were well tolerated in Chinese HVs, and the pharmacokinetic profile of HDC in Chinese HVs was characterized in this study. A single dose of 1.0 mg HDC had a more rapid but similar extent of absorption, a wider distribution, and a little more rapid elimination in Chinese HVs compared with Western HVs. Findings from this study support additional clinical trials for HDC using in Chinese patients. (C) 2015 Elsevier HS Journals, Inc. All rights reserved.

语种英语
WOS记录号WOS:000364270000021
项目编号2012ZX09303019
资助机构Major Project of National Science and Technology "Creation of Major New Drugs" during the Twelfth Five-Year Plan Period
引用统计
被引频次:2[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/54982
专题北京大学第二临床医学院_药剂科
北京大学第二临床医学院_血液科
作者单位1.Peking Univ, Peoples Hosp, Dept Pharm, Beijing 100044, Peoples R China
2.Peking Univ, Peoples Hosp, Inst Hematol, Beijing 100871, Peoples R China
3.Peking Univ, Peoples Hosp, Drug Clin Trial Inst, Beijing, Peoples R China
推荐引用方式
GB/T 7714
Li, Jiapeng,Huang, Xiaojun,Wang, Qian,et al. Pharmacokinetic Properties and Safety Profile of Histamine Dihydrochloride Injection in Chinese Healthy Volunteers: A Phase I, Single-center, Open-label, Randomized Study[J]. CLINICAL THERAPEUTICS,2015,37(10):2352-2364.
APA Li, Jiapeng.,Huang, Xiaojun.,Wang, Qian.,Jing, Shan.,Jiang, Hao.,...&Feng, Wanyu.(2015).Pharmacokinetic Properties and Safety Profile of Histamine Dihydrochloride Injection in Chinese Healthy Volunteers: A Phase I, Single-center, Open-label, Randomized Study.CLINICAL THERAPEUTICS,37(10),2352-2364.
MLA Li, Jiapeng,et al."Pharmacokinetic Properties and Safety Profile of Histamine Dihydrochloride Injection in Chinese Healthy Volunteers: A Phase I, Single-center, Open-label, Randomized Study".CLINICAL THERAPEUTICS 37.10(2015):2352-2364.
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